Cytokine and lipid mediator networks in tuberculosis

Abstract

A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebrafish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here, we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections.

Keywords: cytokines; eicosanoids; host-directed therapy; lipoxins; prostaglandins; tuberculosis.

Fig. 1. Overview of eicosanoid and cytokine-driven effector pathways

Pathways were grouped based on their effector functions (bottom boxes) into pro-(red) or anti-mycobacterial (blue). Upstream inducers of the pathways are depicted in the top box and corresponding receptors signaling triggering downstream functions are designated on the bottom box.

Fig. 2. IL-12 p40 expression is differentially regulated by Type I and Type II IFNs in the lungs of Mtb-infected mice

(A). WT CD45.1/1 mice were lethally irradiated and reconstituted with equal ratios of WT (CD45.1/2) or Ifngr1^−/− or Ifnar1^−/− (CD45.2/2) BM cells and infected with Mtb, as described previously (21, 24). After 8–10 weeks of immune reconstitution, mice were infected with 100–200 CFU via aerosol exposure. This experimental approach allows for direct assessment of WT and gene-deficient cells in the same animal, thereby bypassing potential caveats of WT vs. KO comparisons such as vastly different bacterial loads, inflammatory profiles or pathology. (B). Blue Box; Analysis of donor BM derived CD11c^pos myeloid cells 4 weeks post infection in isolated lung cells marked by CD45.1 and CD45.2 expression and frequency of IL-12/23p40 expression by WT (white circles) or Ifngr1^−/− (KO, blue circles) cells after re-stimulation for 5 h with irradiated Mtb (Irr. Mtb) or without (unstim.). Red Box: Analysis of donor BM-derived CD11c^pos myeloid cells 4 weeks post infection in isolated lung cells marked by CD45.1 and CD45.2 expression and frequency of IL-12/23p40 expression by WT (white circles) or Ifnar1^−/− (KO, red circles) cells after re-stimulation for 5 h with irradiated Mtb (Irr. Mtb) or without (unstim.). Data are representative of two individual experiments with a minimum of three mice each. Each connecting line depicts an individual animal and asterisk (*) denotes significant differences as assessed by a paired student’s t test.

Fig. 3. Cytokine and eicosanoid regulatory networks during Mtb infection

Conceptualization of the regulatory circuits governing the outcome of Mtb infection as discussed in this review. Connections with green arrows denote positive regulation, while red oval-shaped arrowheads reflect negative regulation. References describing the regulatory pathways involved are associated with each line.